Nucleoside derivatives which can be selectively incorporated into viral DNA or RNA to inhibit the replication of viral DNA or RNA, are highly effective agents for treating viral infectious diseases such as herpesvirus, herpes zoster, AIDS, hepatitis, cytomegalovirus and the like. Similarly, such incorporation of nucleoside derivatives into the DNA or RNA of cancer cells can result in tumor cell death and effective treatment of neoplastic diseases. Especially useful are purine derivatives, which have a substituent in the 9-position. These purine derivatives include a large number of significant known compounds having antiviral activity such as acyclovir, ganciclovir, famciclovir, and the like. Also useful for their anticancer activity are purine derivatives such as cladribine (2-CdA), fludarabine, clofarabine, and the like.
Achieving regiospecific and stereoselective glycosylation of purine derivatives at the 9-position is difficult. Glycosylation procedures in which a 2-deoxysugar moiety is coupled with an aglycon invariably provide anomeric mixtures as well as positional isomers, which can result in low yields of the desired nucleoside and often requires troublesome purification protocols. A simplified procedure for N-9 glycosylation that is regiospecific would be highly desirable.
Attempts to enhance N-9 regioselective glycosylation have been made. Gupta et al. (U.S. Patent Application Publication 2004/0039190) describes glycosylation of 6-(acylamido)purines, but notes that the disclosed procedure also produces N-7 glycosylate products. Others have noted that the introduction of larger substituents at C-6 of the purine ring can result in larger ratios of N-9 to N-7 isomer products from simple alkylation reactions (Tetrahedron 1990, 46, 6903). Alarcon et al. (Tetrahedron Lett. 2000, 41, 7211) prepared 2-amino-6-(1,2,4-triazol-4-yl)purine, and reported that alkylation of its sodium salt in DMF with methyl iodide or 1-bromopropane gave the simple N-9 alkyl isomers. Alarcon et al. attributed this selectivity to the introduction of a bulky easily hydrolysable group at C-6 of the purine ring. The use of 6-(acylamido)purines in coupling reactions with sugar derivatives has been performed. Gupta et al. apply potassium salts of 6-(acylamido)purines to prepare 9-glycosyl derivatives of purines that are contaminated with lesser amounts of the 7-glycosyl isomers. Glycosyl coupling with a purine sodium salt in a polar aprotic solvent such as DMF is known to give anomeric mixtures of nucleosides resulting from extensive isomerization of the halo sugar intermediate. Such conditions give stereo- and regioisomeric mixtures as well as extensive sugar decomposition by-products. Gupta et al. use anhydrous THF as a solvent and the strong base potassium hexamethyldisilazide (KHMDS) in toluene to generate potassium salts of 6-(acylamido)purines, followed by addition of the sugar glycosyl chloride derivative. No attempt to enhance the respective solubilities of the 6-(acylamido)purine and sugar derivative was noted.